Breast cancer is the most prevalent cancer globally with ~2.3 million diagnosis per year, presenting a significant healthcare burden. Patients diagnosed with the triple negative subtype of breast cancer (TNBC) have far fewer treatment options and substantially higher mortality rate compared to hormone receptor (ER/PR) and HER2+ breast cancer. Furthermore, TNBC is typically more aggressive with a higher metastatic propensity.
The extracellular matrix (ECM) is an intricate and complex network of proteins and sugars that is present in all tissues. Both the biochemical and biomechanical properties of the ECM define the microenvironment of tissues and organs. One of the major functions of the ECM is to provide signals that regulate cell behaviour to control and shape tissue and organ function. The significant dysregulation of the ECM that typically accompanies solid tumour progression, including in TNBC, leads to the generation of unique cancer-associated matrices which are now seen as a significant facilitator of metastasis through their aberrant modulation of critical intracellular signalling pathways.
The extracellular matrix and metastatic dissemination of solid tumours are intricately linked. Tumour cells secrete and manipulate matrix composition and structure, facilitating their invasion into surrounding tissues and overt colonisation. Furthermore, matrix remodelling induced by cancer cells also modulates metastatic spread and secondary organ colonisation.
Through proteomic profiling of the extracellular matrix secretome of breast cancer, we have identified several new targets that may play a critical role in metastatic dissemination and colonisation of secondary sites. We have identified SPARC (Secreted Protein Acidic and Rich in Cysteine), a matrix proteoglycan as an important matrisomal component associated with overt colonisation of metastatic sites.
Utilising 2D and 3D models of breast cancer, as well as knockout mouse models, ongoing work is elucidating the role of SPARC in relation to tumour progression, metastasis, and response to chemotherapy to determine the potential of developing novel anti-stromal targeting approaches against SPARC as well as its utility as a prognostic biomarker of outcome and predictive biomarker of chemotherapy response.